Analgesia is produced by stimulation of medullary nucleus raphe magnus (NRM), midbrain periaqueductal gray (PAG), diencephalic periventricular gray (PVG), medial basal forebrain, lateral hypothalamus (LH), ventrobasal thalamus (VB), and internal capsule. PAG, PVG and basal forebrain stimulation powerfully inhibited responses of spinal dorsal horn neurons to noxious skin heating, and inhibition was blocked by drugs which disrupt the central action of the neurotransmitter 5-hydroxytryptamine (5-HT, serotonin), suggesting that these areas constitute a functionally homogeneous medial serotonergic inhibitory system. Dorsal horn neurons are also inhibited by stimulation of medial thalamus, LH, contralateral VB, internal capsule and contralateral somatosensory cortex, and basal ganglia. The functional relationship of these latter areas to PAG and PVG, and pathways for inhibition will be studied electrophysiologically. Descending inhibition of dorsal horn nociceptive neurons may be an important mechanism underlying analgesia, a better understanding of which will aid in developing more effective pain therapies. Microelectrodes will be used to record the responses of single lumbar dorsal horn neurons to noxious heat stimuli (50 degrees C) applied to glabrous footpad skin in anesthetized cats. Stimulating electrodes will be stereotaxically positioned at the target brain sites, and electrical stimulus trains applied simultaneously with the noxious skin heat stimulus to determine effects (quantified as the percent reduction in the neuronal heat-evoked response during brain stimulation in relation to the control response without brain stimulation). Effects of stimulation at each site (medial thalamus, LH, VB, cortex, basal ganglia) on neuronal intensity coding for graded noxious heat stimuli, and ability of 5-HT antagonists (methysergide) or depletion (with p-chlorophenylalanine) and the opiate antagonist naloxone to block inhibition, will be compared with similar data on PAG and PVG/basal forebrain stimulation. The possibility that inhibition from PVG and other sites is mediated via activation of a proposed PAG-NRM-spinal inhibitory system will be tested by determining if (a) inhibition is blocked following PAG or NRM lesions, and (b) neurons in PAG and NRM (recorded with microelectrodes in anesthetized cats) are activated by stimulation of PVG and other sites. The possible role of the corticospinal tract in descending inhibition will be investigated.